Stereoselectivity Switch Research Articles

Achiral Counteranion-Induced Reversal of Enantioselectivity in Ni(II)-Catalyzed Friedel-Crafts Alkylation/Annulation of 2-Naphthols.

An achiral counteranion-induced reversal of enantioselectivity in Ni(II)-catalyzed Friedel-Crafts alkylation/annulation of 2-naphthols with β,γ-unsaturated α-keto esters was achieved. Using imidazolidine pyrroloimidazolone pyridine as the ligand and Ni(acac)2 as the Lewis acid, diverse naphthopyran derivatives were obtained in good yields (up to 94% yield) and high enantioselectivities (up to 99% ee). In the presence of Ni(OTf)2 as the Lewis acid, a series of chiral naphthopyran derivatives were obtained in good yields and with a controlled switch in stereoselectivity. DFT calculations reveal that the achiral counteranions regulate H-bonding interactions between counteranions with the N-H of the ligand and the O-H of 2-naphthol.

Reversal of enantioselectivity in cobalt(ii)-catalyzed asymmetric Michael–alkylation reactions: synthesis of spiro-cyclopropane-oxindoles

An asymmetric Michael–alkylation reaction with a reversal of enantioselectivity catalyzed by chiral cobalt complexes is reported, giving spiro-cyclopropane-oxindoles with a complete and controlled switch in stereoselectivity (up to 99% and −98% ee).

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides.

The desymmetrization of meso-vic-diols with a reversal of enantioselectivity catalyzed by chiral pyridine-N-oxides with l-proline as a single source of chirality is reported. With chiral 3-substituted ArPNO C2c and 2-substituted 4-(dimethylamino)pyridine-N-oxide C3b as catalysts, a wide range of monoesters were obtained with satisfactory results with a complete and controlled switch in stereoselectivity (up to 97:3 and 1:99 er). Chiral six-membered carbocyclic uracil nucleosides were generated with excellent enantioselectivities after derivatization. A series of control experiments and density functional theory (DFT) calculations supported that the reaction proceeded in a bifunctional activated manner, where the N-oxide groups and N-H proton of the amides were vital for catalytic reactivity and stereocontrol. The DFT calculation also supported the distance-directed switching of enantioselectivity, in which the l-prolinamide moiety moved from the C3 to C2 position on the pyridine ring, resulting in the H-bond interaction between the amide N-H and OH group of meso-vic-diol also shifted from one hydroxyl group to another.

Insights into Stereoselectivity Switch in Michael Addition-Initiated Tandem Mannich Cyclizations and Their Extension from Enamines to Vinyl Ethers.

Both cis- and trans- tetracyclic spiroindolines are the core of many important biologically active indole alkaloids, but the divergent synthesis of these important motifs is largely hampered by the limited stereoselectivity control. A facile stereoinversion protocol is reported here in Michael addition-initiated tandem Mannich cyclizations for constructing tetracyclic spiroindolines, providing an easy access to two diastereoisomeric cores of monoterpene indole alkaloids with high selectivity. The mechanistic studies including in situ NMR experiments, control experiments, and DFT calculations reveal that the reaction undergoes a unique retro-Mannich/re-Mannich rearrangement including a C-C bond cleavage that is very rare for a saturated six-membered carbocycle. Insights into the stereoinversion process have been uncovered, and the major effects were determined to be the electronic properties of N-protecting groups of the indole with the aid of Lewis acid catalysts. By understanding these insights, the stereoselectivity switching strategy is also smoothly applied from enamine substrates to vinyl ether substrates, which are enriched greatly for the divergent synthesis and stereocontrol of monoterpene indole alkaloids. The current reaction also proves to be very practical and was successfully applied to the gram-scale total synthesis of strychnine and deethylibophyllidine in short routes.

Stereoselective hydrogen atom transfer to acyclic radicals: a switch enabling diastereodivergent borylative radical cascades

Radical cascade reactions are powerful tools to construct structurally complex molecules. However, the stereochemical control of acyclic radical intermediates remains a persistent challenge, due to the low differentiation between the two faces of these species. This hurdle further makes stereodivergent synthesis rather more difficult to be accomplished, in particular for intermediates resulted from complex cascades. Here we report an efficient strategy for stereoselective hydrogen atom transfer (HAT) to acyclic carbon radicals, which are generated via N-heterocyclic carbene (NHC)-boryl radicals triggered addition-translocation-cyclization cascades. A synergistic control by the NHC subunit and a thiol catalyst has proved effective for one facial HAT, while a ZnI2-chelation protocol allows for the preferential reaction to the opposite face. Such a stereoselectivity switch enables diastereodivergent construction of heterocycles tethering a boron-substituted stereocenter. Mechanistic studies suggest two complementary ways to tune HAT diastereoselectivity. The stereospecific conversions of the resulting boron-handled products to diverse functionalized molecules are demonstrated.

Stereoselectivity Switch in the Reduction of α-Alkyl-β-Arylenones by Structure-Guided Designed Variants of the Ene Reductase OYE1.

Ene reductases from the Old Yellow Enzyme (OYE) family are industrially interesting enzymes for the biocatalytic asymmetric reduction of alkenes. To access both enantiomers of the target reduced products, stereocomplementary pairs of OYE enzymes are necessary, but their natural occurrence is quite limited. A library of wild type ene reductases from different sources was screened in the stereoselective reduction of a set of representative α-alkyl-β-arylenones to investigate the naturally available biodiversity. As far as the bioreduction of the ethyl ketone derivatives concerns, the results confirmed the distinctiveness of the OYE3 enzyme in affording the reduced product in the (S) configuration, while all the other tested ene reductases from the Old Yellow Enzymes family showed the same stereoselectivity toward the formation of corresponding (R) enantiomer. A possible determinant role of the “hot spot” residue in position 296 for the stereoselectivity control of these reactions was confirmed by the replacement of Phe296 of OYE1 with Ser as found in OYE3. Further investigations showed that the same stereoselectivity switch in OYE1 could be achieved also by the replacement of Trp116 with Ala and Val, these experimental results being rationalized by structural and docking studies. Moreover, an additive effect on the stereoselectivity of OYE1 was observed when coupling the selected mutations in position 296 and 116, thus providing two extremely enantioselective variants of OYE1 (W116A-F296S, W116V-F296S) showing the opposite stereoselectivity of the wild type enzyme. Lastly, the effects of the mutations on the bioreduction of carvone enantiomers were investigated as well.

Stereoselectivity Switch in the Trapping of Polar Organometallics with Andersen's Reagent-Access to Highly Stereoenriched Transformable Biphenyls.

The trapping of racemic polar carbometallic species with (-)-menthyl ( SS)- p-toluenesulfinate (Andersen's reagent) typically proceeds with a very low level of resolution. In this paper, we describe a strategy that allows access to highly atropo-enriched and functionalizable biphenyls by means of Andersen's reagent under kinetic resolution conditions. In particular, useful enantiopure 2-iodobiphenyls could be obtained and were employed in a challenging hypervalent iodine-catalyzed oxidation reaction.

ChemInform Abstract: N‐Substitution Dependent Stereoselectivity Switch in Palladium Catalyzed Hydroalkynylation of Ynamides: A Regio and Stereoselective Synthesis of Ynenamides.

A highly general palladium catalysed regioselective hydroalkynylation of ynamides for versatile enamide building blocks with an alkyne tether is achieved with an N-substitution dependent stereoselectivity switch under very mild reaction conditions.

ChemInform Abstract: Cyclocarbonylative Sonogashira Reactions of 1‐Ethynylbenzyl Alcohols: Synthesis of 1‐Carbonylmethylene‐1,3‐dihydroisobenzofurans.

In this work, we present a carbonylative Sonogashira reaction of o-ethynyl benzyl alcohols and aryl iodides, followed by a cyclization process to selectively give carbonylmethylene isobenzofurans in high yields and in an atom-economic fashion. The reaction can be carried out in the absence of CuI, with a small amount of PdCl2(PPh3)2 (0.2–0.5 mol-%), using aryl iodides bearing both electron-withdrawing and electron-donating groups. Of the two possible stereoisomeric products, Z-isobenzofuran derivatives were obtained as major products. But, when the reaction was extended to a secondary alcohol, an interesting switch in stereoselectivity was observed.

Cyclocarbonylative Sonogashira Reactions of 1‐Ethynylbenzyl Alcohols: Synthesis of 1‐Carbonylmethylene‐1,3‐Dihydroisobenzofurans

AbstractIn this work, we present a carbonylative Sonogashira reaction of o‐ethynyl benzyl alcohols and aryl iodides, followed by a cyclization process to selectively give carbonylmethylene isobenzofurans in high yields and in an atom‐economic fashion. The reaction can be carried out in the absence of CuI, with a small amount of PdCl2(PPh3)2 (0.2–0.5 mol‐%), using aryl iodides bearing both electron‐withdrawing and electron‐donating groups. Of the two possible stereoisomeric products, Z‐isobenzofuran derivatives were obtained as major products. But, when the reaction was extended to a secondary alcohol, an interesting switch in stereoselectivity was observed.

N-Substitution dependent stereoselectivity switch in palladium catalyzed hydroalkynylation of ynamides: a regio and stereoselective synthesis of ynenamides.

A highly general palladium catalysed regioselective hydroalkynylation of ynamides for versatile enamide building blocks with an alkyne tether is achieved with an N-substitution dependent stereoselectivity switch under very mild reaction conditions.

Stereoselectivity Switch between Zinc and Magnesium Initiators in the Polymerization of rac-Lactide: Different Coordination Chemistry, Different Stereocontrol Mechanisms

The preparation and characterization of several zinc and magnesium complexes bearing chiral aminophenolate ligands, [(S)- or (R)-L]ZnN(SiMe3)2 (1, 2), [(S)- or (R)-L]ZnOtBu (3, 4) and [(S)- or (R)-L]MgN(SiMe3)2 (5, 6) ((S)- or (R)-L = (S)- or (R)-2-{N-benzyl-N-[(1-nbutyl-2-pyrrolidinyl)methyl]}aminomethyl-4-methyl-6-tritylphenolate), have been reported. While the X-ray diffraction studies as well as the NMR spectroscopic data revealed that zinc and magnesium silylamido complexes possess similar structures both in the solid state and in solution, their catalytic performance toward rac-LA polymerization exhibited significant difference. The replacement of zinc center by magnesium realized an interesting stereoselectivity switch from isoselective (Pm = 0.80) to heteroselective (Pr = 0.81). The reactions of enantiopure zinc complexes 1 and 2 with (S)-methyl lactate or (R)-tert-butyl lactate resulted in the target lactate complexes 7–9 as a mixture of two diastereomers, but in different ratios. Two typical zin...

Stereocontrolled lithiation/trapping of chiral 2-alkylideneaziridines: investigation into the role of the aziridine nitrogen stereodynamics.

The origin of the stereoselectivity in the lithiation/trapping of 2-alkylideneaziridines bearing a chiral group as the nitrogen substituent was investigated. Optimal reaction conditions were discovered by in situ FT-IR monitoring. In addition, it has been found that the solvent and the alkene substitution pattern are important factors able to impart a switch in stereoselectivity. While lithiation of the alkylideneaziridine ring flanked by either a fully substituted or a Z-configured alkene pendant occurs stereoselectively in THF, in contrast unsubstituted 2-methyleneaziridine undergoes lithiation in toluene with the opposite sense of stereoinduction. Lithiation experiments, on deuterium labelled 2-alkylideneaziridines, confirmed the configurational stability of the lithiated intermediates. A model based on complexation and proximity effects was proposed to rationalize the reactivity. This model assumes that slowly equilibrating N-invertomers undergo deprotonation (lithiation) at different rates and that the stereochemical outcome is established during the deprotonation step.

Remarkable stereoselectivity switch in synthesis of carbonyl substituted N2-arylamidrazones with low lipophilicity

Reaction of carbonyl substituted hydrazonoyl chlorides with amines usually leads to Z-configured amidrazone derivatives via nucleophilic substitution of the chlorine atom. Surprisingly, N,N-dimethylcarboxamide substituted hydrazonoyl chlorides yielded E-amidrazones when dialkylamines were used as nucleophilic reagent. The lipophilicities of the obtained amidrazones were found to be drastically reduced compared to their corresponding carboxanilides.

The first facile stereoselectivity switch in the polymerization of rac-lactide—from heteroselective to isoselective dialkylgallium alkoxides with the help of N-heterocyclic carbenes

The reaction of N-heterocyclic carbene (NHC) with dimeric dialkylgallium alkoxides, acting as nonselective or heteroselective catalysts in the polymerization of rac-LA, leads to highly active and isoselective monomeric Me(2)Ga(NHC)OR catalysts, resulting for the first time in the facile switch of stereoselectivity.

ChemInform Abstract: Switch in Stereoselectivity Caused by the Isocyanide Structure in the Rhodium‐Catalyzed Silylimination of Alkynes.

AbstractReaction of terminal alkynes with isocyanides and hydrosilanes proceeds smoothly in the presence of a Rh catalyst to give, after imine hydrolysis, the β‐silyl‐α,β‐unsaturated aldehydes (IV)/(V).

Switch in Stereoselectivity Caused by the Isocyanide Structure in the Rhodium-Catalyzed Silylimination of Alkynes

The reaction of terminal alkynes with hydrosilanes and tert-alkyl isocyanides in the presence of Rh(4)(CO)(12) gives (Z)-β-silyl-α,β-unsaturated imines in good yields. On the other hand, the use of aryl isocyanides in place of tert-alkyl isocyanides leads to the formation of E isomers.

Stereoselective Synthesis of the Octahydronaphthalene Unit of Integramycin via an Intramolecular Diels−Alder Reaction

[reaction: see text] The racemic cis-decalin core fragment 30 of integramycin was synthesized by a sequence involving a highly diastereoselective intramolecular Diels-Alder reaction of triene 24. A remarkable switch in stereoselectivity occurred upon changing the dienophile unit of 24 from (Z)- to (E)-geometry.

Versatile stereocontrol in kinetic resolution of a diphenylphosphinyl-protected α-amino aldehyde by reaction with chiral phosphonates

In kinetic resolutions of the racemic aldehyde 1 by reaction with chiral phosphonates of type 2, all of which contain the same chiral auxiliary in the same enantiomeric form, any of the four diastereomers 3a, 3b, 4a or 4b can be obtained as the main product by an appropriate choice of reaction parameters (geometric selectivities from 66:34 to 98:2, diastereomer ratios between 93:7 and ≥99:1). The switch in stereoselectivity observed when KHMDS or NaHMDS is used as base instead of KHMDS/18-crown-6 is rationalized as resulting from a change in influence of the aldehyde α-stereocenter from Felkin-Anh-Eisenstein to chelation control.